This invention relates to novel marzipan-like compositions in unit dosage form containing an anion exchange resin. These compositions comprise almond paste and an anion exchange resin (e.g. cholestyramine, colestipol). An optional, preferred ingredient is psyllium.
Although effective in reducing serum cholesterol, anion exchange resins such as cholestyramine and colestipol have an unpleasant taste and mouthfeel. The present invention compositions greatly improve the aesthetics of these anion exchange resins. These compositions have excellent texture, mouthfeel and palatability, and are well tolerated by the intestinal tract.
High blood cholesterol levels are associated with life threatening cardiac diseases. Cholestyramine and colestipol are drugs used in treating hypercholesterolemia. These drugs are known as basic anion exchange resins. They help to lower blood cholesterol levels apparently by binding to bile acids in the intestine. It is believed that this in turn causes an increase in hepatic metabolism of cholesterol to replenish the bile acids lost to complexation with the anion exchange resins.
Cholestyramine is usually dosed using from four to thirty-two grams, given once daily or divided into two, three, or four equal intervals. At the present time cholestyramine is commercially available as Questran.RTM. (manufactured by the Mead Johnson division of Bristol-Myers Company) in a four gram unit dose powder packet or in bulk powder, and as Cholybars.RTM. (manufactured by Parke Davis) wherein one chewable bar contains four grams of cholestyramine. [Physicians Desk Reference, 44th Edition, pages 726-729 and 1595-1597 (1990).]
Colestipol is usually administered daily in two to four equally divided doses of fifteen to thirty grams. Colestipol is commercially available under the tradename Colestid.RTM. (colestipol hydrochloride granules, manufactured by The Upjohn Company). It is sold in a five gram unit dose powder packet or in bulk powder. [Physicians Desk Reference, 44th Edition, pages 433 and 2216-2218 (1990)].
While the benefits of anion exchange resins are well known and appreciated, the aesthetics (e.g., mouthfeel; taste; throat sticking) are considered by many users to be very unpleasant. Cholestyramine can give the perception of sticking to the back of the mouth and throat upon ingestion, and may be viewed as leaving a fishy taste in the mouth. Colestipol has an astringent taste and a sandy, gritty texture which sticks to the mouth and teeth after ingestion. Obviously, poor aesthetics raise concern about how closely patients will comply with any treatment regimen involving these drug therapies.
Several attempts have been made to improve the palatability of anion exchange resins. Patents which disclose such attempts include: East German Patent DD 249,634 published Sep. 16, 1987 by V&B Chemukombinat Bitterfeld (describes grinding a basic anionic exchanger such as cholestyramine in a wet state and spraying on an aqueous solution of pectin during drying); Great Britain Patent Specification Number 1,446,352, published Aug. 18, 1976 by Merck & Co., Inc. (describes an oral pharmaceutical composition in liquid form comprising a coacervate of a hydrophilic colloid of a cellulose derivative, such as sodium carboxymethyl cellulose, and cholestyramine); French Medical Patent 6,888 M published Jun. 4, 1964 by Mead Johnson & Company (describes dry mixing acacia gum with cholestyramine resin to aid in making the extreme astringency of cholestyramine disappear); U.S. Pat. No. 4,895,723, issued to Amer et al. Jan. 23, 1990 (describes orally ingestible compositions for reduction of blood cholesterol levels comprising cholestyramine and a water-soluble carbohydrate syrup such as high fructose corn syrup or a liquid alcohol polyol humectant such as glycerine); U.S. Pat. No. 4,843,098, issued to Shaw et al. Jun. 27, 1989, U.S. Pat. No. 4,818,539, issued to Shaw et al. Apr. 4, 1989, and U.S. Pat. No. 4,790,991, issued to Shaw et al. Dec. 13, 1989, divisions of U.S. Pat. No. 4,747,881, issued to Shaw et al. May 31, 1988 (relating to preswelled substantially anhydrous hydrocolloid aggregate such as carboxymethyl cellulose with a size range of about 4 to about 70 U.S. mesh, and a substrate comprising dietary fiber and/or drug, such as cholestyramine); U.S. Pat. No. 4,778,676, issued to Yang et al. Oct. 18, 1988 (describes a chewable delivery system for actives comprising an active, such as cholestyramine, pre-coated with at least one material selected from the group consisting of lecithin, polyoxyalkenes having chain lengths of about four carbons or less, glycerides having a melting point of 100.degree. C. or less, polyalkylene glycols having a molecular weight of 3,700 or less, synthetic and natural waxes and mixtures thereof, and a confectionery matrix comprising a binder system of gelatin and a humectant material); U.S. Pat. No. 3,974,272, issued to Polli et al. Aug. 10, 1976 (describes a palatable oral coacervate composition containing cholestyramine and a modified gum selected from the group consisting of hydrophillic colloid of cellulosive material and charged anionic gum in an aqueous medium); and U.S. Pat. No. 3,499,960, issued to Macek et al. (describes coating the cholestyramine particles with an acrylic polymer crosslinked with allylsucrose).
Other publications relating to therapeutic use of cholestyramine or psyllium include the following. European Patent Application Publication No. 323,666, published Jul. 12, 1989 by The Procter & Gamble Company. This publication describes methods and compositions for reducing blood cholesterol levels by oral administration of psyllium and cholestyramine, optionally in combination with polyol polyesters. It is also stated therein that "cholestyramine resin, administered orally, has sometimes been associated with constipation and preparations containing cholestyramine often have an unpleasant sandy or gritty quality. Advantageously, these problems associated with cholestyramine are alleviated when the psyllium and/or psyllium plus optional polyol polyesters are employed therewith."
U.S. Pat. No. 4,824,672, issued to Day et al. Apr. 25, 1989, describes an orally utilizable pharmaceutical composition comprising gel-forming fiber (such as guar gum, psyllium seed, pectin, glucomannan, oat and barley) and a mineral salt (such as calcium carbonate, magnesium carbonate, or potassium carbonate) said to be administered to humans to reduce serum cholesterol levels.
Management of Hypercholesterolemia. Approach to Diet and Drug Therapy, Stein, The American Journal of Medicine, Vol. 87(4A) (1989) advises patients who experience constipation from the use of cholestyramine or colestipol (bile acid sequestrants used to decrease blood cholesterol levels) to take a bulk laxative, such as psyllium fiber, with the evening dose of sequestrant if other dietary changes do not alleviate the problem of constipation.
The Effect of Psyllium Hydrocolloid and Cholestyramine on Hepatic Bile Lipid Composition in Man, Behrer et al., Henry Ford Hospital Medical Journal, Vol. 21(1) (1973), examined the effects of psyllium hydrocolloid and of cholestyramine on the total cholesterol, total phospholipid, total bile salt, cholate, chenodeoxycholate, and deoxycholate concentrations of 6 post-cholecystectomy patients.
Other U.S. patents that describe compositions in which psyllium is an optional or essential ingredient include: U.S. Pat. No 4,766,004, to Moskowitz, issued Aug. 23, 1988 (describes dietary fiber supplement compositions comprising whole psyllium husks having a particle size of from 12 to 70 mesh, food grade vegetable fat which is a solid at room temperature, sweetening agent and flavoring agent); and U.S. Pat. No. 4,698,232, to Sheu et al., issued Oct. 6, 1987 (describes fiber-containing confectionery compositions comprising dietary fiber pretreated with a lubricant, a foamed matrix, and an amorphous matrix).
Naturacil.RTM. (sold by Mead Johnson) is an artificial chocolate flavored, caramel-like laxative product containing psyllium. The ingredients listed for this product include sugar, glycerin, nonfat milk, and partially hydrogenated vegetable oil.
U.S. Pat. No. 4,871,557 to Linscott, issued Oct. 3, 1989 describes a granola bar containing supplemental dietary fiber. Psyllium is listed as one of many sources of supplemental dietary fiber. Flavoring agents, toasted rolled oats, chopped almonds, and coconut flakes are among many materials mentioned as optional granola ingredients. U.S. Pat. No. 4,619,831, to Sharma, issued Oct. 28, 1986, describes dietary fiber products comprising insoluble dietary fiber (92-98.5%) coated or enrobed with soluble dietary fiber (1.5-8%; psyllium is mentioned as one of many soluble fibers). U.S. Pat. No. 5,009,916, to Colliopoulos, issued Apr. 23, 1991, describes high fiber food compositions comprising psyllium and other dietary fiber sources.
West German Patent Specification 2,430,509, published Jan. 15, 1976 by Hypolab S.A., Genf. (Schweiz), describes preparing compositions containing bulk laxatives (including psyllium mucilloid) in the form of a cake. The cake dough is prepared and baked in molds to produce cakes having thickness of 3-6 mm.
Further, U.S. Pat. No. 4,568,557, issued Feb. 4, 1986 and U.S. Pat. No. 4,673,578, issued Jun. 16, 1987, both to Becker et al., describe high dietary fiber-containing snack food products and methods comprising from about 5% to about 30% by weight of dietary fiber, soaked in food grade oil, for example, admixed with peanut butter such that the peanut oil becomes absorbed by the fiber, and further mixed with a compound coating.
Other documents include: U.S. Pat. No. 4,511,561, to Madaus et al., issued Apr. 16, 1985; Goodman & Gilman, The Pharmacologic Basis of Therapeutics, Sixth Edition, 1004 (1980); Garvin et al., Proc. Soc. Exp. Biol. Med., 120, 744-746 (1965); Forman et al., Proc. Soc. Exp. Biol. Med., 127, 1060-1063 (1968); Anderson et al., Fed. Proc., 46, 877 (1987); Anderson et al., Am. J. Gastroenterol., 81,907-919 (1986); and Fagerberg, Curr. Ther. Res., 31, 166 (1982).
Although a considerable amount of research has been aimed at developing palatable compositions containing an anion exchange resin, a great need still exists for compositions that provide therapeutic benefit while maintaining an agreeable texture and taste, thereby encouraging patient compliance with a prescribed treatment regimen. It has been discovered that combining an anion exchange resin (such as cholestyramine or colestid) in a marzipan composition helps to mask the unpleasant taste and mouthfeel associated with these resins. It has also been discovered that an anion exchange resin can be prepared in the form of a marzipan-like composition with psyllium as a preferred optional ingredient. These compositions are believed to offer an even greater enhancement to the texture, mouthfeel and taste of compositions containing an anion exchange resin, as well as enhanced efficacy.
An object of the present invention is therefore to provide convenient, portable and highly palatable compositions that deliver an anion exchange resin in a marzipan-like medium. Another object of this invention is to provide a method for treating hypercholesterolemia by administering to humans a pharmaceutical composition comprising an anion exchange resin in a marzipan-like composition. A further object of the invention is to enhance the acceptance and compliance with a treatment regimen involving anion exchange resin by hypercholesterolemic patients by improving through the present invention the palatability and overall mouthfeel of compositions containing an anion exchange resin. Another object of the present invention is to provide anion exchange resin treatment for hypercholesterolemia that is more efficacious and/or more readily tolerated by the gastrointestinal tract.
These and other objects of the present invention will become readily apparent from the detailed description which follows.
All percentages and ratios used herein are by weight, and all measurements are made at 25.degree. C., unless otherwise specified.